Thermodynamic Capacity of Quantum Processes.
Thermodynamics imposes restrictions on what state transformations are possible. In the macroscopic limit of asymptotically many independent copies of a state-as for instance in the case of an ideal gas-the possible transformations become reversible and are fully characterized by the free energy. In this Letter, we present a thermodynamic resource theory for quantum processes that also becomes reversible in the macroscopic limit, a property that is especially rare for a resource theory of quantum channels. We identify a unique single-letter and additive quantity, the thermodynamic capacity, that characterizes the "thermodynamic value" of a quantum channel, in the sense that the work required to simulate many repetitions of a quantum process employing many repetitions of another quantum process becomes equal to the difference of the respective thermodynamic capacities. On a technical level, we provide asymptotically optimal constructions of universal implementations of quantum processes. A challenging aspect of this construction is the apparent necessity to coherently combine thermal engines that would run in different thermodynamic regimes depending on the input state. Our results have applications in quantum Shannon theory by providing a generalized notion of quantum typical subspaces and by giving an operational interpretation to the entropy difference of a channel.


Selective Egg Cannibalism in Sinella Curviseta (Collembola: Entomobryidae).
Sinella curviseta eggs less than 24 hours of age are smooth; older developing eggs are rough. An experiment was concluded to analyze egg cannibalism in unisexual populations exposed to eggs on both types. This experiment demonstrated that egg consumption (i) averaged .03 eggs per animal per hour, (ii) occurs at a significantly higher rate in females than in males, and (iii) is almost completely (99%) confined to smooth eggs. As smooth eggs include very young eggs and faulty eggs of any age, smooth eggs have a lower probability of reproductive success than rough ones. Animals encounter in a clutch first smooth eggs with less chance of hatching; later, smooth eggs with a still probability of success (as more developing ones have become rough); and finally, during the final 72% of the period of exposure to a clutch, smooth eggs whose probability of hatching is effectively zero. It is efficient resource utilization to ingest these eggs.


Severe hyperglycemia in an HIV clinic: preexisting versus drug-associated diabetes mellitus.
We determined the frequency and clinical nature of severe hyperglycemia in a university clinic for HIV-1-infected patients. The medical records of 1392 adult HIV-infected patients were reviewed for cases of severe hyperglycemia, defined as two or more serum glucose values >250 mg/dl or diabetes treatment during clinic care. Demographic information, family histories of diabetes mellitus, body weights, CD4+ lymphocyte counts, and use of corticosteroids, megestrol acetate, pentamidine, or didanosine were recorded for subjects meeting the case definition. Comparisons were made between preexisting diabetic (group 1) and incident hyperglycemic cases (group 2). Less than 2% of the total clinic population experienced severe hyperglycemia: 12 in group 1 and 13 in group 2. Group 2 had lower body weights (mean, 70.6 kg versus 90.0 kg; p < 0.05) and more advanced HIV disease (mean CD4 count, 79/mm3 versus 550/mm3; p < 0.05) than group 1. Group 2 cases had evidence of drug-associated hyperglycemia; four cases demonstrated hyperglycemia coinciding with large fluctuations in weight during megestrol therapy. Among megestrol recipients, cases did not differ from noncases in demographics, weight, or CD4 count. Severe hyperglycemia is uncommon in adult HIV-infected patients. Approximately one half of these patients have preexisting diabetic conditions; many of the remainder may have drug-induced hyperglycemia, especially as a result of corticosteroids or megestrol acetate.


REAL-TIME MECHANISTIC BAYESIAN FORECASTS OF COVID-19 MORTALITY.
The COVID-19 pandemic emerged in late December 2019. In the first six months of the global outbreak, the US reported more cases and deaths than any other country in the world. Effective modeling of the course of the pandemic can help assist with public health resource planning, intervention efforts, and vaccine clinical trials. However, building applied forecasting models presents unique challenges during a pandemic. First, case data available to models in real-time represent a non-stationary fraction of the true case incidence due to changes in available diagnostic tests and test-seeking behavior. Second, interventions varied across time and geography leading to large changes in transmissibility over the course of the pandemic. We propose a mechanistic Bayesian model (MechBayes) that builds upon the classic compartmental susceptible-exposed-infected-recovered (SEIR) model to operationalize COVID-19 forecasting in real time. This framework includes non-parametric modeling of varying transmission rates, non-parametric modeling of case and death discrepancies due to testing and reporting issues, and a joint observation likelihood on new case counts and new deaths; it is implemented in a probabilistic programming language to automate the use of Bayesian reasoning for quantifying uncertainty in probabilistic forecasts. The model has been used to submit forecasts to the US Centers for Disease Control, through the COVID-19 Forecast Hub. We examine the performance relative to a baseline model as well as alternate models submitted to the Forecast Hub. Additionally, we include an ablation test of our extensions to the classic SEIR model. We demonstrate a significant gain in both point and probabilistic forecast scoring measures using MechBayes when compared to a baseline model and show that MechBayes ranks as one of the top 2 models out of 10 submitted to the COVID-19 Forecast Hub. Finally, we demonstrate that MechBayes performs significantly better than the classical SEIR model.


Transhumanist Genetic Enhancement: Creation of a 'New Man' Through Technological Innovation.
The transhumanist project of reshaping human beings by promoting their improvement through technological innovations has a broad agenda. This study focuses on the enhancement of the human organism through genetic modification techniques. Transhumanism values and a discussion of their philosophical background provide a framework to understand its ideals. Genetics and ethics are employed to assess the claims of the transhumanist program of human enhancement. A succinct description of central concepts in genetics and an explanation of current techniques to edit the human genome serve to assess the capabilities and limitations of editing techniques. Potential benefits and liabilities of human enhancement through genome editing are discussed to appraise its feasibility. Ethical considerations of genome editing inform a reflection on the implications of introducing heritable changes in the genome of individuals. It is concluded that the transhumanist program is underpinned by a large number of hypotheses rather than by sufficient evidence.


Corrector design with active vase mirrors that allows a fixed telescope to access a large region of the sky.
We investigate a family of two-mirror correctors to compensate for the aberrations of a parabolic mirror observing at a large angle from the zenith. We constrain our designs to optical elements that can be built with currently available technology. The secondary and the tertiary mirrors are warped by Zernike polynomials, which we know can be generated with active vase mirrors. The performances of these corrector designs are usable for imagery.


Lessons learnt from evidence-based approach of using chinese herbal medicines in liver cancer.
This paper is a systematic review of evidence-based studies of the effectiveness of Chinese herbal medicine (CHM) in the treatment of liver cancer. After a detailed analysis of the literature, five animal studies and four human clinical trials met the criteria for inclusion. Analysis revealed that results of the clinical trials, whilst encouraging, need to be interpreted with caution as problems with study designs may lead to apparent benefits being attributable to various forms of bias. However, as each of the CHM agents used in these studies appeared to be potentially beneficial, further well-designed and controlled randomized clinical trials are warranted. The second part of this review focused on the lessons learned from the relationships between Traditional Chinese Medicine (TCM) theory, TCM Syndrome Differentiation, and modern scientific understanding of mechanisms of action of CHM agents. The understanding of TCM Syndrome Differentiation may allow identification of different patterns of disharmony and may provide important guidance to the prescription of CHM. Furthermore, quality control using both biological and chemical fingerprinting of CHM is important to ensure batch-to-batch consistency to deliver sustained therapeutic benefit. Also, careful assessment of herb-drug interactions is paramount for safety and integrative use of western chemotherapeutic and CHM agents.


Prevalence of peanut and tree nut allergy in the United States determined by means of a random digit dial telephone survey: a 5-year follow-up study.
Allergy to peanuts and tree nuts (TNs) is the leading cause of fatal and near-fatal food allergic reactions. Peanut allergy appears to be increasing in prevalence. We sought to determine the prevalence of self-reported peanut and TN allergy among the general population of the United States in 2002 by sex and age and to compare the results with prevalence estimates obtained 5 years earlier. We performed a nationwide, cross-sectional, random telephone survey by using a standardized questionnaire. A total of 4855 households participated (53% participation rate), representing a census of 13,493 individuals. Peanut allergy, TN allergy, or both was self-reported in 166 (1.2%; 95% CI, 1.0%-1.4%) individuals in 155 (3.2%; 95% CI, 2.7%-3.7%) households, overall prevalence rates similar to those reported in 1997. Also similar to the 1997 survey, the severity level was high, with 79% reporting respiratory or multiple organ system reactions and 66% experiencing more than 5 lifetime reactions. Despite the severity and reaction frequency, only 74% of the children and 44% of the adults sought evaluation for the allergy, and fewer than half who did were prescribed self-injectable epinephrine. Applying conservative rules to adjust for persons with unconvincing reactions and a false-positive rate of the survey instrument (7%), a final prevalence estimate of 1.04% (95% CI, 0.9%-1.24%) was obtained. A male predominance of peanut-TN allergy was reported in children younger than 18 years (1.7% vs 0.7%, P =.02), and a female predominance was reported among adults (1.7% vs 0.9%, P =.0008). Although the rate of peanut allergy, TN allergy, or both was not significantly different from 1997 to 2002 among adults, the rate increased from 0.6% to 1.2% among children, primarily as a result of an increase in reported allergy to peanut (0.4% in 1997 to 0.8% in 2002, P =.05). Self-reported peanut allergy has doubled among children from 1997 to 2002, and peanut allergies, TN allergies, or both continue to be reported by more than 3 million Americans. Considering that reactions are severe and the allergy is persistent, these allergies represent an increasing health concern.


Duodenocolic fistula due to safety pin ingestion.
The authors describe the case of a 16-month-old boy with benign duodenocolic fistula due to safety pin ingestion who presented with abdominal pain, diarrhea and weight loss. Etiology, symptomatology, diagnosis and management are discussed and the literature is reviewed. Early diagnosis and surgical management are necessary to avoid serious morbidity.


How Important Are Social Support, Expectations and Coping Patterns during Cardiac Rehabilitation.
Purpose. To investigate the predictive role of relevant social and psychosocial determinants on emotional distress among patients after cardiac rehabilitation. Methods. A longitudinal prospective study examined short-term (6 months) and long-term (2 years) impact of predictors on anxiety and depression complaints in 183 patients with 6-months follow-up data attending a four-week rehabilitation stay at the Krokeide Centre in Bergen, Norway. The patients mainly suffered from coronary heart disease. Emotional distress, coping, social support, socioeconomic status, and negative expectations were measured by means of internationally validated questionnaires. A composite score of anxiety and depression complaints was used as the outcome measure in the study. Results. This study revealed that task-oriented coping improved emotional status in long-term followup, and negative expectations were associated with emotional distress in short-term followup. A higher socioeconomic status and more social support predicted improved emotional status in short- as well as long-term followup. Conclusions. Fewer negative expectations and functional coping along with social support are important factors for the prevention of emotional distress after cardiac disease. Such elements should be addressed and encouraged in patients during cardiac rehabilitation.


[Criteria of estimation of state forensic-medical expert activity administration].
Criteria of estimation of state forensic medical activity administration were systematized and their content was considered. New integral index of administration efficiency - index of technological efficiency - was developed and proved.


Correlation between ocular biometric parameters and corneal endothelium in a sample of young Egyptian adults.
To evaluate the normative values of corneal endothelial cell parameters within a group of healthy young Egyptian adults using specular microscopy and to examine any correlations between endothelial parameters and refractive or biometric parameters. In this cross-sectional study, specular microscopy was used to study the right eyes of 150 healthy young volunteers and evaluated endothelial cell parameters, including cellular density, hexagonality (HEX), and coefficient of variation (CV) at 15 different points on the back corneal surface, which were later grouped into the central zone and either four quadrants or three annular zones. The same eyes underwent refractive and biometric assessments. Hundred fifty healthy adults were examined, and the age ranged from 20 to 30 years, with a median of 23 (interquartile range, 21‒27) years. The mean (standard deviation) of central cell density was 2902.7 (270.7) cells/mm2. The superior paracentral area had the lowest mean density (2895.8 cells/mm2), but the highest mean HEX (67.7%), while the inferior peripheral area had the highest mean density (3100.5 cells/ mm2) but the lowest mean HEX (64%). The difference in cell density among the three annular zones was not statistically significant (P = 0.365). However, HEX and CV in the central and paracentral zones differed statistically significantly from those of the peripheral zone (P < 0.001 and P = 0.014, respectively). Weak but non-significant correlations were detected between endothelial cell density and all measured refractive and biometric parameters. The findings of this study provided useful normative biometric and specular data in a specific age group and a specific population, and could be useful in planning intraocular surgery in young Egyptian adults. However, future longitudinal studies with a larger sample could refine more endothelial cell parameter specifications over time.


Diagnosis of famine: a discursive contribution.
This paper recommends the incorporation of an additional discursive dimension in famine diagnosis that draws on the number of reports referring to famine in the United Nations Office for the Coordination of Humanitarian Affairs (OCHA)'s ReliefWeb database. Present-day diagnostic tools already apply the principle of triangulation with multiple indicators; the addition of a discursive diagnostic dimension would enable even more refined analysis, allowing more forcefully for the incorporation of the aspect of change. The newly devised discursive famine indices are used both to identify famines--in Ethiopia (2000), Malawi (2002), and Somalia (2011)--and to analyse key socioeconomic determinants of famine. The study finds that income (or poverty) together with state fragility appear to be the major determinants of cross-country variations in famine reporting, while political regimes do not appear to have any independent effect. The indices appear largely robust with regard to concerns about cross-country, semantic, and temporal biases.


Food Availability in Different Food Environments Surrounding Schools in a Vulnerable Urban Area of Santiago, Chile: Exploring Socioeconomic Determinants.
The analysis of the food environment is used to identify areas with gaps in the availability of healthy foods and can be used as a public policy assessment tool. In recent decades, Chile has implemented several strategies and regulations to improve food environments, with encouraging results. Little is known about the scope of these measures in socially vulnerable environments. This study is part of a project that seeks to build an integrated intervention model for healthy school environments in a vulnerable area of Santiago, Chile. The objective of this study was to evaluate the availability of healthy and unhealthy foods around schools and the relationship between it and socioeconomic determinants of the school community in the Chilean context. A cross-sectional study to measure the food environment of informal markets (street food), formal markets (stores), and institutions (schools) was conducted in and around 12 schools (100 m surrounding schools) in a vulnerable urban area of Santiago, Chile. A lack of healthy foods was observed, which was related to some socio-economic determinants and the multidimensional poverty was the most relevant. The diagnosis of food environments around schools can represent an important target for governments to implement policies focused at improving the availability of healthy foods.


Left ventricular blood flow patterns at rest and under dobutamine stress in healthy pigs.
Intracardiac blood flow patterns are affected by the morphology of cardiac structures and are set up to support the heart's pump function. Exercise affects contractility and chamber size as well as pre- and afterload. The aim of this study was to test the feasibility of four-dimensional phase contrast cardiovascular MRI under pharmacological stress and to study left ventricular blood flow under stress. 4D flow data were successfully acquired and analysed in 12 animals. During dobutamine infusion, heart rate and ejection fraction increased (82 ± 5 bpm versus 124 ± 3 bpm/46 ± 9% versus 65 ± 7%; both p < 0.05). A decrease in left ventricular end-diastolic volume (72 ± 14 mL versus 55 ± 8 mL; p < 0.05) and end-systolic volume (40 ± 15 mL versus 19 ± 6 mL; p < 0.05) but no change in stroke volume were observed. Trans-mitral diastolic inflow velocity increased under dobutamine and the trajectory of inflowing blood was directed towards the anterior septum with increased inflow angle (26 ± 5°) when compared with controls (15 ± 2°). In 5/6 animals undergoing stress diastolic vortices developed later, and in 3/6 animals vortices collapsed earlier with significantly smaller cross-sectional area during diastole. The vorticity index was not affected. Under the stress condition direct flow (% ejection within the next heart beat) increased from 43 ± 6% to 53 ± 8%. 4D MRI blood flow acquisition and analysis are feasible in pig hearts under dobutamine-induced stress. Flow patterns characterized by high blood velocity and antero-septally oriented diastolic inflow as well as decreased ventricular volumes are unfavourable conditions for diastolic vortex development under pharmacological stress, and cardiac output is increased by a rise in heart rate and directly ejected left ventricular blood volume.


The effect of nitrogen supply on growth and water-use efficiency of xylem-tapping mistletoes.
Xylem-tapping mistletoes are known to have normally a higher rate of transpiration and lower water-use efficiency than their hosts. The relationships between water relations, nutrients and growth were investigated for Phoradendron juniperinum growing on Juniperus osteosperma (a non-nitrogen-fixing tree) and for Phoradendron californicum growing on Acacia greggii (a nitrogen-fixing tree). Xylem sap nitrogen contents were approximately 3.5 times higher in the nitrogen-fixing host than in the non-nitrogen-fixing host. The results of the present study show that mistletoe growth rates were sevenfold greater on a nitrogen-fixing host. At the same time, however, the differences in water-use efficiency between mistletoes and their hosts, which were observed on the non-nitrogen-fixing host did not exist when mistletoes were grown on hosts with higher nitrogen contents in their xylem sap. Growth rates and the accumulation of N, P, K, and Ca as well as values for carbon-isotope ratios of mistletoe tissues support the hypothesis that the higher transpiration rates of mistletoes represent a nitrogen-gathering mechanism.


Envelope protein synthesis and inhibition of cell division in Escherichia coli during inactivation of the B subunit of DNA gyrase.
The rates of synthesis of inner and outer membrane proteins of Escherichia coli K12 during inhibition of cell division have been studied. When cell division was inhibited, either by treatment of wild-type cells with the antibiotic clorobiocin (an inhibitor of the B subunit of DNA gyrase) or by a temperature shift of a gyrB-ts mutant, a 40% reduction in the rate of synthesis of total outer membrane protein relative to that of the inner membrane was observed. When a gyrB-ts mutant was shifted to high temperature under conditions which allowed continued cell division, this large reduction in the rate of synthesis of outer membrane protein relative to inner membrane protein was not observed. In contrast to the results obtained with clorobiocin, inhibition of cell division by the beta-lactam antibiotic cefuroxime did not cause any detectable disturbance in the rate of synthesis of either inner or outer membrane protein. This demonstrates that inhibition of septum formation per se does not perturb synthesis of envelope protein. The data obtained are consistent with a model in which the rate of synthesis and therefore expansion of outer membrane is one of many conditions which must be satisfied before septum formation can occur. The results are discussed in relation to such a model, and to previous findings which have shown that the rate of synthesis of outer membrane proteins displays a linear mode with an abrupt doubling in rate at a discrete point in the cell cycle.


The opioid growth factor, [Met5]-enkephalin, inhibits DNA synthesis during recornification of mouse tail skin.
Opioid peptides serve as tonically active negative growth regulators in renewing and regenerating epithelia. To examine the involvement of opioids in renewal of the stratum corneum after tape stripping of tail skin, C57BL/6 J mice were given systemic injections of the potent opioid antagonist, naltrexone (NTX, 20 mg/kg i.p.) following injury. Blockade of opioid-receptor interaction by NTX for 4 h resulted in an elevation of 36-66% in basal cell DNA synthesis measured 24 h after injury. Injection of the endogenous opioid peptide, [Met5]-enkephalin (OGF, 10 mg/kg i.p.) 4 h before termination, suppressed radiolabelled thymidine incorporation in the basal cell layer by 37-46% at 24 h after wounding. The magnitude of the effects on DNA synthesis of OGF, but not NTX, depended on the timing of administration with respect to injury. OGF maximally depressed basal cell labelling (72%) when given 16 h after tape stripping. Concomitant administration of naloxone (10 mg/kg) with OGF blocked the inhibition of DNA synthesis; naloxone alone at the dosage utilized had no effect on cell labelling. Both OGF and its receptor, OGFr, were detected by immunocytochemistry in the basal and suprabasal cell layers, but not the cornified layer of tape stripped and uninjured tail skin. These results indicate: (a) a native opioid peptide and its receptor are expressed in epidermal cells of injured and uninjured mouse tail skin; (b) removal of the stratum corneum by tape stripping does not disrupt the function of the endogenous opioid growth system; (c) the proliferative response to wounding of the tail is tonically inhibited by the receptor-mediated action of an endogenous opioid peptide; and (d) DNA synthesis by basal cells can be elevated by disrupting opioid peptide receptor interactions.


Effects of the active constituents of Catha edulis on the neuromuscular junction.
(-)-Cathinone and d-norpseudoephedrine (DNE) in the dose range 0.2-1.2 mg/ml produced a reduction in contractions of skeletal muscle, evoked by direct and indirect electrical stimulation and antagonised the facilitatory action of physostigmine on the neuromuscular junction; but failed to antagonise a partial blockade induced by d-tubocurarine (dTb) as occurs with norepinephrine or epinephrine. The local anaesthetic actions of (-)-cathinone and DNE were found to be almost equivalent to that of lignocaine. These results indicate that (-)-cathinone and DNE may have a direct blocking action on the neuromuscular junction, which is independent of cholinergic and adrenergic transmission.


A theoretical investigation of magnetic susceptibility measurement of diamagnetic liquids using a Michelson interferometer.
In this paper, we investigate the potential of using a Michelson interferometer to measure the magnetic susceptibility of liquids. The theoretical basis for this measurement technique is presented, including the relevant equations and models used to analyze the data. The proposed method involves using a ring magnet to deform the liquid and passing a laser beam through the liquid to measure the resulting interference pattern using the interferometer. The deformation of the liquid caused by the known magnetic field of the ring magnet can be used to calculate the magnetic susceptibility of the liquid. The feasibility and potential advantages of this method are discussed, including the possibility of high-precision measurements and the applicability of the technique to various fields.


Characteristics of deaths occurring in children's hospitals: implications for supportive care services.
End-of-life care is an important yet underdeveloped component of pediatric hospital services. We sought 1) to describe the demographics of children who die in children's hospitals, 2) to describe the prevalence of complex chronic conditions (CCCs) among these cases, and 3) to test the hypotheses that cases with a greater number of CCC diagnoses experience longer periods both of mechanical ventilation and of hospitalization before death. Design and Methods. We identified all deaths of patients 0 to 24 years old that occurred in the 60 hospitals contributing discharge data to the National Association of Children's Hospitals and Related Institutions data consortium for the years 1991, 1994, and 1997. We classified discharge diagnoses into 9 major categories of CCCs (cardiovascular, neuromuscular, malignancy, respiratory, renal, metabolic, gastrointestinal, hematologic/immunologic, and other congenital/genetic). Of the 13 761 deaths identified, 42% had been admitted between 0 and 28 days of life, 18% between 1 and 12 months, 25% between 1 and 9 years, and 15% between 10 and 24 years. Fifty-three percent were white, 20% were black, and 9% were Hispanic. The principal payer was listed as a governmental source for 42% and a private insurance company for 35%. Based on all the discharge diagnoses recorded for each case, 40% had no CCC diagnosis, 44% had diagnoses representing 1 major CCC category, 13% had diagnoses representing 2 CCC categories, and 4% had diagnoses representing 3 or more CCC categories. Among cases that had no CCC diagnoses, the principal diagnoses were related to prematurity and newborn disorders for 32% of these cases, injuries and poisoning for 26%, and an assortment of acute and infectious processes for the remaining 42%. Mechanical ventilation was provided to 66% of neonates, 40% of infants, 36% of children, and 36% of adolescents. Cases with CCCs were more likely than non-CCC cases to have been mechanically ventilated (52% vs 46%), and to have been ventilated longer (mean: 11.7 days for CCC cases vs 4.8 days for non-CCC cases). The median duration of hospitalization was 4 days, while the mean was 16.4 days. After adjustment for age, sex, year, and principal payer, compared with patients with no CCC diagnoses, those with 1 major CCC category had a significantly lower hazard of dying soon after admission (hazard ratio [HR]: 0.60; 95% confidence interval [CI]: 0.57-0.62), those with 2 CCC categories even lower (HR: 0.53; 95% CI: 0.50-0.57), and those with 3 or more CCC categories the lowest hazard of rapid death (HR: 0.51; 95% CI: 0.46-0.57). This trend of diminishing hazard of rapid death was significant across the 3 groups of children with 1 or more CCCs. Children's hospitals care for a substantial number of dying patients, who differ widely by age and medical conditions. Children who die in the hospital with CCCs are more likely to experience longer periods of mechanical ventilation and hospitalization before death.


Directed microtubule growth, +TIPs, and kinesin-2 are required for uniform microtubule polarity in dendrites.
in many differentiated cells, microtubules are organized into polarized noncentrosomal arrays, yet few mechanisms that control these arrays have been identified. For example, mechanisms that maintain microtubule polarity in the face of constant remodeling by dynamic instability are not known. Drosophila neurons contain uniform-polarity minus-end-out microtubules in dendrites, which are often highly branched. Because undirected microtubule growth through dendrite branch points jeopardizes uniform microtubule polarity, we have used this system to understand how cells can maintain dynamic arrays of polarized microtubules. we find that growing microtubules navigate dendrite branch points by turning the same way, toward the cell body, 98% of the time and that growing microtubules track along stable microtubules toward their plus ends. Using RNAi and genetic approaches, we show that kinesin-2, and the +TIPS EB1 and APC, are required for uniform dendrite microtubule polarity. Moreover, the protein-protein interactions and localization of Apc2-GFP and Apc-RFP to branch points suggests that these proteins work together at dendrite branches. The functional importance of this polarity mechanism is demonstrated by the failure of neurons with reduced kinesin-2 to regenerate an axon from a dendrite. we conclude that microtubule growth is directed at dendrite branch points and that kinesin-2, APC, and EB1 are likely to play a role in this process. We propose that kinesin-2 is recruited to growing microtubules by +TIPS and that the motor protein steers growing microtubules at branch points. This represents a newly discovered mechanism for maintaining polarized arrays of microtubules.


Observations of the liquid-crystal analog of the abrikosov phase.
Freeze-fracture transmission electron micrographs of the smectic A(*) phase confirm the twist grain boundary model of Renn and Lubensky. The fracture surface has an undulating structure with a 0.5-micrometer helical pitch parallel to 4.1-nanometer smectic layers. The layers are disrupted by a lattice of screw dislocations oriented normal to the helical axis. Optical diffraction shows that rotation of smectic blocks occurs in discrete steps of about 17 degrees ; hence, the screw dislocations are 14 to 15 nanometers apart and the grain boundaries are 24 nanometers apart. These observations show that the SmA(*) phase is the liquid-crystal analog of the Abrikosov phase in superconductors.


Perinatal transmission of hepatitis B virus.
Transmission of hepatitis B virus from carrier mothers to their infants seems most likely to occur during birth. Both cord blood and breast milk have been found to be positive (in 35% and 72% of cases respectively) for hepatitis B surface antigen (HBsAg), but they do not appear to play an important role in transmission. To control this problem high-risk women should be tested during pregnancy for HBsAg. The infants of infected women should be given several doses of hepatitis B immunoglobulin starting at birth. In less developed regions, where hepatitis B is endemic, administration of the immunoglobulin in combination with vaccine, or even the vaccine alone, may be preferable in order to provide infants with lasting protection.


Evaluation of the Effectiveness of Compression Garments on Autonomic Nervous System Recovery After Exercise.
The aim of this investigation was to evaluate the recovery pattern of a whole-body compression garment on hemodynamic parameters and on autonomic nervous system (ANS) activity after a swimming performance. Ten young male athletes were recruited and tested in 2 different days, with and without wearing the garment during the recovery phase. After a warm-up of 15 minutes, athletes were instructed to perform a maximal 400-m freestyle swimming event, and then time series of beat-to-beat intervals for heart rate variability (HRV), baroreflex sensitivity (BRS), and hemodynamic parameters were recorded for 90 minutes of recovery. The vagally mediated high frequency (HF) power of R-R intervals, NN50, and pNN50 showed a faster recovery due to the costume; meanwhile, the low frequency (LF) spectral component of HRV (LFRR) index of sympathetic modulation of the heart and the LF:HF ratio and BRS alpha index (αLF) were augmented in control than in garment condition. When athletes wore the swimsuit, cardiac output was increased and the returning of the blood to the heart, investigated as stroke volume, was kept constant because of the reduction of the total peripheral resistances. During control condition, heart rate (HR) was restored back to baseline value 20 minutes later with respect to garment condition, confirming that the swimsuit recover faster. The effectiveness of the swimsuit on ANS activity after a maximal aerobic performance has been shown with a greater recovery in terms of HRV and hemodynamic parameters. Baroreflex sensitivity was reduced in both conditions, maybe due to prolonged vasodilatation that may have also influenced the postexercise hypotension.


Designing M13 Bacteriophage and Fe-Nanonest Self-Assembly System for Universal and Facile Preparation of Metal Single Atoms as Stable Mimicking Enzymes.
Metal single-atom catalysts (MSACs) possess multiple advantages in chemical synthesis; their efficient fabrication routes, however, remain a challenge to date. Here, an interdisciplinary design using M13 bacteriophage virus as a biotemplate to carry Fe nanoclusters, which we figuratively call "Fe-nanonests", is proposed to enable facile and versatile synthesis of MSACs. The feasibility and generality of this self-assembly method was demonstrated by the observation of six different metal single atoms (MSAs) including Ag, Pt, Pd, Zn, Cu, and Ni. With Pd as a representative, key factors dominating the fabrication were determined. The Pd single atoms exhibited excellent horseradish peroxidase (HRP)-like activity, which was further improved by 50% via genetic editing of the M13 pVIII protein terminals. Excellent stability was also observed in the quantification of acid phosphatase, a cancer predictor. X-ray absorption near-edge structure spectroscopy has been applied to the analysis of Pd single atoms as well, and the Pd-N4 coordination explained the mechanism of high HRP-like catalytic activity. The MSAs synthesized by the M13 phage and Fe-nanonest self-assembly method show promising prospects in non-cold-chain medical detection applications.


Patients' views of quality of life: transforming the knowledge base of nursing.
Nurses in advanced practice roles are leaders of the transformative process that will further define the discipline of nursing as a human science of lived experience. Essential to the transformation is a change in nursing's knowledge base, a change that defines practice and research as participative, open, and quality enhancing. To demonstrate the transformation of knowledge in practice, the authors present findings from a qualitative research study guided by the nursing theory called human becoming. The purpose of the study was to enhance understanding of quality of life for patients receiving acute psychiatric care. A descriptive exploratory design was used to guide data gathering and analysis of 24 people. Findings are presented in themes that represent quality-of-life issues, including feelings of loss and shifting value priorities, the complex nature of relationships that ease and upset, and the hopes that fuel the intense struggle to go on living. Directions for practice and research are suggested.


Differential roles of trans-phosphorylated EGFR, HER2, HER3, and RET as heterodimerisation partners of MET in lung cancer with MET amplification.
MET is a receptor tyrosine kinase (RTK) whose gene is amplified in various tumour types. We investigated the roles and mechanisms of RTK heterodimerisation in lung cancer with MET amplification. With the use of an RTK array, we identified phosphorylated RTKs in lung cancer cells with MET amplification. We examined the roles and mechanisms of action of these RTKs with immunoprecipitation, annexin V binding, and cell migration assays. We identified epidermal growth factor receptor (EGFR), human EGFR (HER)2, HER3, and RET in addition to MET as highly phosphorylated RTKs in lung cancer cells with MET amplification. Immunoprecipitation revealed that EGFR, HER2, HER3, and RET each formed a heterodimer exclusively with MET and that these associations were markedly reduced in extent by treatment with a MET kinase inhibitor. RNA interference-mediated depletion of EGFR, HER2, or HER3 induced apoptosis in association with inhibition of AKT and ERK signalling pathways, whereas depletion of HER2 or RET inhibited both cell migration and STAT3 signalling. Our data suggest that heterodimers of MET with EGFR, HER2, HER3, or RET have differential roles in tumour development, and they provide new insight into the function of trans-phosphorylated RTKs as heterodimerisation partners of MET in lung cancer with MET amplification.


Pectin methylesterase, metal ions and plant cell-wall extension. The role of metal ions in plant cell-wall extension.
The study of pectin methylesterase and wall-loosening enzyme activities in situ, as well as the estimation of the electrostatic potential of the cell wall, suggest a coherent picture of the role played by metal ions and pH in cell-wall extension. Cell-wall growth brings about a decrease of local proton concentration because the electrostatic potential difference (delta psi) of the wall decreases. This in turn activates pectin methylesterase, which restores the initial delta psi value. This process is amplified by the attraction of metal ions in the polyanionic cell-wall matrix. The amplification process is basically due to the release of enzyme molecules that were initially bound to 'blocks' of carboxy groups. This increase of metal-ion concentration also results in the activation of wall-loosening enzymes. Moreover, the apparent 'inhibition' of pectin methylesterase by high salt concentrations may be considered as a device which prevents the electrostatic potential from becoming too high.


Notoginsenoside R1 ameliorates the inflammation induced by amyloid‑β by suppressing SphK1‑mediated NF‑κB activation in PC12 cells.
Alzheimer's disease (AD) is the most common type of age‑related dementia, and causes progressive memory degradation, neuronal loss and brain atrophy. The pathological hallmarks of AD consist of amyloid‑β (Aβ) plaque accumulation and abnormal neurofibrillary tangles. Amyloid fibrils are constructed from Aβ peptides, which are recognized to assemble into toxic oligomers and exert cytotoxicity. The fibrillar Aβ‑protein fragment 25‑35 (Aβ25‑35) induces local inflammation, thereby exacerbating neuronal apoptosis. Notoginsenoside R1 (NGR1), one of the primary bioactive ingredients isolated from Panax notoginseng, exhibits effective anti‑inflammatory and anti‑oxidative activities. However, NGR1 pharmacotherapies targeting Aβ‑induced inflammation and cell injury cascade remain to be elucidated. The present study investigated the effect and mechanism of NGR1 in Aβ25‑35‑treated PC12 cells. NGR1 doses between 250 and 1,000 µg/ml significantly increased cell viability suppressed by 20 µM Aβ25‑35 peptide treatment. Notably, the present study demonstrated that Aβ25‑35 peptide‑induced sphingosine kinase 1 (SphK1) signaling activation was reduced after NGR1 treatment, further inhibiting the downstream NF‑κB inflammatory signaling pathway. In addition, administration of SphK1 inhibitor II (SKI‑II), a SphK1 inhibitor, also significantly reduced Aβ25‑35 peptide‑induced apoptosis and the ratio of NF‑κB p‑p65/p65. Furthermore, SphK1 knockdown in PC12 cells using small interfering RNA alleviated Aβ‑induced cell apoptosis and inflammation, suggesting a pivotal role of SphK1 signaling in the anti‑inflammatory effect of NGR1. In summary, NGR1 alleviated inflammation and apoptosis stimulated by Aβ25‑35 by inhibiting the SphK1/NF‑κB signaling pathway and may be a promising agent for future AD treatment.


Hyperglycemia in patients with hematologic malignancies.
Patients with hematologic malignancies are at high risk for hyperglycemia due to factors such as frequent exposure to glucocorticoids, immunosuppressants, total parenteral nutrition, and medical stress. Hyperglycemia in these patients has been associated with poor outcomes including increased risk of infection, organ dysfunction, durability of remission, graft-versus-host disease, and mortality. However, the appropriate glucose targets are not well established, and there are few prospective data assessing whether glucose control improves outcomes. HbA1c should be interpreted with caution in patients with hematologic malignancies, due to inaccuracies imposed by disordered hematopoiesis and frequent transfusions, and short-term perturbations imposed by acute illness or medications. Management of diabetes or glucocorticoid-induced hyperglycemia in the hospital generally requires insulin therapy, which is tailored based upon nutritional needs, baseline glucose control, and concomitant factors such as type and dose of glucocorticoid administration. Close follow-up and adjustment of therapy, ideally with the assistance of patient self-titration algorithms, is required after discharge. Patients are at increased long-term risk for developing diabetes and therefore should undergo regular screening.


Is there a role for retinoids to treat minimal residual disease in neuroblastoma?
A variety of pre-clinical and clinical data point toward high drug levels of retinoids being required to achieve optimal efficacy against neuroblastoma. The results of the Kohler trial reported in this issue demonstrate that low-dose 13-cis-RA does not have clinical efficacy against neuroblastoma in a setting of minimal residual disease. A comparison of the Kohler trial with the US CCG trial provides clinical evidence that high-dose levels of retinoids are optimal for treating minimal residual disease in neuroblastoma. The comparison of high-dose and low-dose 13-cis-RA studies in neuroblastoma suggests the intriguing possibility that high dose, pulse schedules of other retinoids could be effective as therapeutic and chemopreventive agents in diseases where low-dose, chronic retinoid administration was not effective. Pre-clinical and perhaps clinical studies of the latter concept should be considered.


The role of adenovirus 36 as a risk factor in obesity: the first clinical study made in the fatty tissues of adults in Turkey.
Obesity which developes due to multifactorial reasons, was associated recently with human Adenovirus-36 (Ad-36). The aim of this study was to investigate the prevalence of Ad-36 antibodies in obese adults and also to investigate the DNA of Ad-36 in their adipose tissue. In this cross-sectional and case-control based study, 49 obese adults, with BMI ≥ 30 kg/m(2), and 49 non-obese adults, with BMI ≤ 25 kg/m(2), applied for esthetic purposes and were included in this study as patient and control groups, respectively. Adipose tissue samples, obtained by the lipoaspiration method, were studied by single-step PCR and nested-PCR methods. Simultaneously, the presence of Ad-36 antibodies and serum leptin and adiponectin levels were assessed by serum neutralization assay (SNA) and ELISA, respectively. Serum samples which didn't cause a cytopathic effect at ≥ 1:8 were accepted as positive. Ad-36 antibody was detected in 6 (12.2%) of 49 patients by SNA and was statistically significant (p < 0.05). Ad-36 DNA was not detected in any of the adipose tissue samples of the patient or control groups. Mean BMI and leptin levels were higher in the Ad-36-positive group, while adiponectin levels were found to be lower in the Ad-36-positive group. Although no statistically significant difference was found in cholesterol and triglyceride levels between the two groups (p > 0.05), lower mean serum cholesterol and triglyceride levels were found in the Ad-36-positive patients. In conclusion, we couldn't detect Ad-36 DNA in adipose tissue; however, we detected significantly higher Ad-36 antibody levels in the obese group compared to the non-obese group, according to the both univariant and multivariant analyses, suggesting that Ad-36 may play a role in obesity. There is a need for new and extended serial, particularly cohort and human-based, studies in order to have a clear understanding of the Ad-36-obesity relationship.


Protein disorder is positively correlated with gene expression in Escherichia coli.
We considered, on a global scale, the relationship between the predicted fraction of protein disorder and the RNA and protein expression in Escherichia coli. Fraction of protein disorder correlated positively with both measured RNA expression levels of E. coli genes in three different growth media and with predicted abundance levels of E. coli proteins. Though weak, the correlation was highly significant. Correlation of protein disorder with RNA expression did not depend on the growth rate of E. coli cultures and was not caused by a small subset of genes showing exceptionally high concordance in their disorder and expression levels. Global analysis was complemented by detailed consideration of several groups of proteins.


Antepartum A1C, maternal diabetes outcomes, and selected offspring outcomes: an epidemiological review.
Between 1989 and 2004, the prevalence of gestational diabetes mellitus (GDM) in the United States increased by 122%. Glycated haemoglobin, as measured by haemoglobin A1C (A1C), can potentially identify pregnant women at high risk for adverse outcomes associated with GDM including macrosomia and post-partum glucose intolerance. Our objective was to systematically review the literature with respect to A1C levels during pregnancy and associated maternal and offspring outcomes. We used MEDLINE to identify relevant publications from 1975 to 2009. We included articles if they met the following criteria: original full text articles in English; primary exposure of antepartum A1C; women with GDM at baseline or who developed GDM during the study; primary outcome of GDM, insulin use, post-partum abnormal glucose or type 2 diabetes (T2DM), birthweight, macrosomia or large for gestational age. Case series and case reports were excluded. Twenty studies met our criteria. A1C at GDM diagnosis was positively associated with post-partum abnormal glucose. Women with post-partum T2DM or impaired glucose tolerance had mean A1C at GDM diagnosis higher than those with normal post-partum glucose (P ≤ 0.002) and a 1% increase in A1C at GDM diagnosis was associated with 2.36 times higher odds of post-partum abnormal glucose 6 weeks after delivery [95% confidence interval 1.19, 4.68]. The association of A1C and birthweight varied substantially between studies, with correlation coefficients ranging from 0.11 to 0.51. A1C, a less burdensome and costly measure than an oral glucose tolerance test, appears to be an attractive measure for identifying women at high risk of adverse outcomes associated with GDM.


Compliant substrates mitigate the senescence associated phenotype of stress induced mesenchymal stromal cells.
Mesenchymal stromal cells (MSCs) are a promising cell population for musculoskeletal cell-based therapies due to their multipotent differentiation capacity and complex secretome. Cells from younger donors are mechanosensitive, evidenced by changes in cell morphology, adhesivity, and differentiation as a function of substrate stiffness in both two- and three-dimensional culture. However, MSCs from older individuals exhibit reduced differentiation potential and increased senescence, limiting their potential for autologous use. While substrate stiffness is known to modulate cell phenotype, the influence of the mechanical environment on senescent MSCs is poorly described. To address this question, we cultured irradiation induced premature senescent MSCs on polyacrylamide hydrogels and assessed expression of senescent markers, cell morphology, and secretion of inflammatory cytokines. Compared to cells on tissue culture plastic, senescent MSCs exhibited decreased markers of the senescence associated secretory phenotype (SASP) when cultured on 50 kPa gels, yet common markers of senescence (e.g., p21, CDKN2A, CDKN1A) were unaffected. These effects were muted in a physiologically relevant heterotypic mix of healthy and senescent MSCs. Conditioned media from senescent MSCs on compliant substrates increased osteoblast mineralization compared to conditioned media from cells on TCP. Mixed populations of senescent and healthy cells induced similar levels of osteoblast mineralization compared to healthy MSCs, further indicating an attenuation of the senescent phenotype in heterotypic populations. These data indicate that senescent MSCs exhibit a decrease in senescent phenotype when cultured on compliant substrates, which may be leveraged to improve autologous cell therapies for older donors.


Risk factors and patterns of household clusters of respiratory viruses in rural Nepal.
Viral pneumonia is an important cause of death and morbidity among infants worldwide. Transmission of non-influenza respiratory viruses in households can inform preventative interventions and has not been well-characterised in South Asia. From April 2011 to April 2012, household members of pregnant women enrolled in a randomised trial of influenza vaccine in rural Nepal were surveyed weekly for respiratory illness until 180 days after birth. Nasal swabs were tested by polymerase chain reaction for respiratory viruses in symptomatic individuals. A transmission event was defined as a secondary case of the same virus within 14 days of initial infection within a household. From 555 households, 825 initial viral illness episodes occurred, resulting in 79 transmission events. The overall incidence of transmission was 1.14 events per 100 person-weeks. Risk of transmission incidence was associated with an index case age 1-4 years (incidence rate ratio (IRR) 2.35; 95% confidence interval (CI) 1.40-3.96), coinfection as initial infection (IRR 1.94; 95% CI 1.05-3.61) and no electricity in household (IRR 2.70; 95% CI 1.41-5.00). Preventive interventions targeting preschool-age children in households in resource-limited settings may decrease the risk of transmission to vulnerable household members, such as young infants.


LKB1 suppresses proliferation and invasion of prostate cancer through hedgehog signaling pathway.
Activation of the hedgehog (Hh) signaling pathway has been implicated in the development of many human malignancies. Hh signaling target genes, such as patched (PTCH), smoothened (SMO) and sonic hedgehog (SHH), are markers of Hh signaling activation in most Hh-associated tumors. The protein kinase LKB1 has been shown to slow proliferation and induce cell-cycle arrest in many cell lines. However, the function of LKB1 in prostate cancer development remains largely unclear. In this study, the expression of LKB1 in human prostate cancer tissue samples and prostate cancer cell lines was detected, and the effects of LKB1 on prostate cancer cell proliferation and invasion were evaluated. Moreover, the influence of LKB1 on target genes of the Hh signaling pathway was analyzed. The results indicated that knockdown of LKB1 expression by RNA interference promoted cell proliferation, colony formation and invasion. Meanwhile, we observed that LKB1 siRNA increased the expression of factors related to Hh signaling reporter activity in prostate cancer cells, including PTCH, SMO and SHH. These findings suggest that LKB1 is a putative tumor suppressor gene in prostate cancer, and that LKB1 is negatively correlated with the expression of Hh signaling related transcription factors. Our results suggest that LKB1 may inhibit tumorigenesis by regulating the Hh signaling pathway in certain cancers.


Legionella pneumophila EnhC is required for efficient replication in tumour necrosis factor alpha-stimulated macrophages.
Legionella pneumophila enhC(-) mutants were originally identified as being defective for uptake into host cells. In this work, we found that the absence of EnhC resulted in defective intracellular growth when dissemination of intracellular bacteria to neighbouring cells was expected to occur. No such defect was observed during growth within the amoeba Dictyostelium discoideum. Culture supernatants containing the secreted products of infected macrophages added to host cells restricted the growth of the DeltaenhC strain, while tumour necrosis factor alpha (TNF-alpha), at concentrations similar to those found in macrophage culture supernatants, could reproduce the growth restriction exerted by culture supernatants on L. pneumophilaDeltaenhC. The absence of EnhC also caused defective trafficking of the Legionella-containing vacuole in TNF-alpha-treated macrophages. EnhC was shown to be an envelope-associated protein largely localized to the periplasm, with its expression induced in post-exponential phase, as is true for many virulence-associated proteins. Furthermore, the absence of EnhC appeared to affect survival under stress conditions, as the DeltaenhC mutant was more susceptible to H(2)O(2) treatment than the wild-type strain. EnhC therefore is a unique virulence factor that is required for growth specifically when macrophages have heightened potential to restrict microbial replication.


Diabetic retinopathy and cognitive decline in older people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study.
Cerebral microvascular disease associated with type 2 diabetes may exacerbate the effects of aging on cognitive function. A considerable homology exists between the retinal and cerebral microcirculations; a hypothesized association between diabetic retinopathy (DR) and cognitive decline was examined in older people with type 2 diabetes. In the population-based Edinburgh Type 2 Diabetes Study, 1,046 men and women aged 60-75 years with type 2 diabetes underwent standard seven-field binocular digital retinal photography and a battery of seven cognitive function tests. A general cognitive ability score (g) was generated by principal components analysis. The Mill-Hill Vocabulary Scale was used to estimate premorbid cognitive ability. DR was graded using a modification of the Early Treatment of Diabetic Retinopathy Scale. After age and sex adjustment, a significant relationship was observed with increasing severity of DR (none, mild, and moderate to severe) for most cognitive measures. Participants with moderate-to-severe retinopathy had the worst g and the worst performances on the individual tests. There was a significant interaction between sex and retinopathy for g. In male subjects, the associations of retinopathy with g (and with tests of verbal fluency, mental flexibility, and processing speed but not memory and nonverbal reasoning) persisted (P < 0.05) when further adjusted for vocabulary (to estimate lifetime cognitive decline), depression, sociodemographic characteristics, cardiovascular risk factors, and macrovascular disease. DR was independently associated with estimated lifetime cognitive decline in older men with type 2 diabetes, supporting the hypothesis that cerebral microvascular disease may contribute to their observed accelerated age-related cognitive decline. A sex interaction with stronger findings in men requires further confirmation.


Review: DNA Barcoding and Chromatography Fingerprints for the Authentication of Botanicals in Herbal Medicinal Products.
In the last two decades, there has been a tremendous increase in the global use of herbal medicinal products (HMPs) due to their claimed health benefits. This has led to increase in their demand and consequently, also, resulted in massive adulteration. This is due to the fact that most of the traditional methods cannot identify closely related species in a process product form. Therefore the urgent need for simple and rapid identification methods resulted in the discovery of a novel technique. DNA barcoding is a process that uses short DNA sequence from the standard genome for species identification. This technique is reliable and is not affected by external factors such as climates, age, or plant part. The difficulties in isolation of DNA of high quality in addition to other factors are among the challenges encountered using the DNA barcoding in the authentication of HMP. These limitations indicated that using DNA barcoding alone may ineffectively authenticate the HMP. Therefore, the combination of DNA barcoding with chromatographic fingerprint, a popular and generally accepted technique for the assessment and quality control of HMP, will offer an efficient solution to effectively evaluate the authenticity and quality consistency of HMP. Detailed and quality information about the main composition of the HMPs will help to ascertain their efficacy and safety as these are very important for quality control.


Mechanism of CcdA-Mediated Rejuvenation of DNA Gyrase.
Most biological processes involve formation of transient complexes where binding of a ligand allosterically modulates function. The ccd toxin-antitoxin system is involved in plasmid maintenance and bacterial persistence. The CcdA antitoxin accelerates dissociation of CcdB from its complex with DNA gyrase, binds and neutralizes CcdB, but the mechanistic details are unclear. Using a series of experimental and computational approaches, we demonstrate the formation of transient ternary and quaternary CcdA:CcdB:gyrase complexes and delineate the molecular steps involved in the rejuvenation process. Binding of region 61-72 of CcdA to CcdB induces the vital structural and dynamic changes required to facilitate dissociation from gyrase, region 50-60 enhances the dissociation process through additional allosteric effects, and segment 37-49 prevents gyrase rebinding. This study provides insights into molecular mechanisms responsible for recovery of CcdB-poisoned cells from a persister-like state. Similar methodology can be used to characterize other important transient, macromolecular complexes.


Ontogeny of temperature-regulated heat shock protein 70 synthesis in preimplantation bovine embryos.
Development of the preimplantation embryo is very susceptible to disruption by heat shock. As embryos proceed through development, they acquire resistance to heat shock, perhaps because they become transcriptionally active and can respond to environmental changes by undergoing transcriptionally-regulated cellular adaptation. Objectives were to determine the ontogeny of heat shock protein 70 (HSP70) synthesis in preimplantation bovine embryos and to ascertain whether heat-induced increases in HSP70 in embryos are caused by environmental alterations in gene expression. Exposure of bovine embryos to heat shock induced synthesis of a 68 kDa form of HSP70 called HSP68 as early as the two-cell stage of development. Induction of HSP68 was alpha-amanitin independent at the two-cell stage but was blocked by alpha-amanitin as early as the early four-cell stage. Therefore, heat-induced synthesis of HSP68 is regulated at the level of transcription at a time before the major round of embryonic genome activation is considered to occur. Two other constitutive HSP70 molecules were identified called heat shock cognates (HSC) 71 and 70; both proteins were synthesized during all stages of development from the two-cell to hatched blastocyst stages. However, heat-induced synthesis of HSC71 and HSC70 was not evident until the expanded blastocyst stage. In conclusion, environmental signals can activate gene expression before the major round of embryonic genome activation occurs in bovine embryos. Moreover, differences in thermal sensitivity of early embryos to heat shock is not caused by an inability to synthesize HSP70, suggesting that other mechanisms are involved in developmental acquisition of thermotolerance.


Intra-tumor heterogeneity: lessons from microbial evolution and clinical implications.
Multiple subclonal populations of tumor cells can coexist within the same tumor. This intra-tumor heterogeneity will have clinical implications and it is therefore important to identify factors that drive or suppress such heterogeneous tumor progression. Evolutionary biology can provide important insights into this process. In particular, experimental evolution studies of microbial populations, which exist as clonal populations that can diversify into multiple subclones, have revealed important evolutionary processes driving heterogeneity within a population. There are transferrable lessons that can be learnt from these studies that will help us to understand the process of intra-tumor heterogeneity in the clinical setting. In this review, we summarize drivers of microbial diversity that have been identified, such as mutation rate and environmental influences, and discuss how knowledge gained from microbial experimental evolution studies may guide us to identify and understand important selective factors that promote intra-tumor heterogeneity. Furthermore, we discuss how these factors could be used to direct and optimize research efforts to improve patient care, focusing on therapeutic resistance. Finally, we emphasize the need for longitudinal studies to address the impact of these potential tumor heterogeneity-promoting factors on drug resistance, metastatic potential and clinical outcome.


Single SLM full-color holographic three-dimensional video display based on image and frequency-shift multiplexing.
A single spatial-light-modulator (SLM) full-color holographic 3-D video display based on image and frequency-shift multiplexing (IFSM) is proposed. In the frequency-shift multiplexing (FSM), three-color holograms are multiplied with their respective phase factors for shifted-separations of their corresponding frequency-spectrums on the Fourier plane. This FSM process, however, causes three-color images to be reconstructed at the center-shifted locations depending on their multiplied phase factors. Center-shifts of those color images due to the FSM can be balanced out just by generation of three-color holograms whose centers are pre-shifted to the opposite directions to those of the image shifts with the novel-look-up-table (NLUT) based on its shift-invariance property, which is called image-shift multiplexing (ISM). These image and frequency-shifted holograms are then multiplexed into a single color-multiplexed hologram and loaded on the SLM, and from which a full-color 3-D image can be reconstructed on the optical 4-f lens system without any color dispersion just by employing a simple pinhole filter mask. Fourier-optical analysis and experiments with 3-D objects in motion confirm the feasibility of the proposed system.


[Imotivated laughter: report of 3 cases].
The authors present three cases where the involuntary, imotivated laughter was a distinct finding. The first patient was a 29-year-old engineer, who had had several bursts of neurologic deficits, either sensitive or motor, which recovered almost completely and was diagnosed as suffering from multiple sclerosis. During and after one of the episodes he presented involuntary laughter and has been like this since then, albeit in much less extension. The second patient was a 35-year-old housewife, who presented several episodes of brain infarction in both hemispheres which were considered as being the result of arteritis. No specific collagen disease was found. The CAT scan showed several hypodense areas in both hemispheres. The third patient was a 52-year-old man of Japanese ancestry who presented three years ago a sudden ischemic stroke with difficulty in the speech and left sided weakness, followed by bursts of imotivated laughter, which persisted since then. Subsequently he had another stroke. He is hypertensive and diabetic. The authors searched the literature for the different causes of involuntary laughter. The occurrence in multiple sclerosis, although reported by several authors is by no means a common finding. In the literature available no case of cerebral arteritis with involuntary laughter could be found. The pathophysiology of this rare symptom was discussed.


Is high weight status associated with pediatric forearm fractures requiring anatomic reduction?
High weight status is associated with increased forearm fracture risk but its relationship to severity of fracture has not been evaluated. We compared the epidemiology of children's forearm fractures treated with fracture reduction to those not treated with reduction, hypothesizing that high weight status would be significantly associated with need for reduction. This is a case-control study including Washington, DC children, ages 2 to 17 years, treated for isolated forearm fractures in an urban, tertiary care pediatric emergency department from 2003 to 2006. Descriptive statistics and logistic regression were conducted to compare patients with forearm fracture reductions to nonintervention controls. Of 888 forearm fractures, 330 (37.2%) required reduction (cases) whereas 558 (64.8%) did not (controls). Cases were more likely than controls to be male [adjusted odds ratio, 1.67 (95% confidence interval, 1.11-2.50)] and to have experienced a more severe mechanism of trauma [adjusted odds ratio, 2.11 (95% confidence interval, 1.14-3.90)]. The groups did not differ in weight status, age, or race/ethnicity. The need for reduction among children with forearm fractures is significantly associated with male sex and major mechanisms of trauma but not with high weight status. Strategies to reduce severe forearm fractures should focus on preventing major mechanisms of trauma.


Use of an Indeterminate Range in HIV Early Infant Diagnosis: A Systematic Review and Meta-Analysis.
Expanded access to HIV antiretrovirals has dramatically reduced mother-to-child transmission of HIV. However, there is increasing concern around false-positive HIV test results in perinatally HIV-exposed infants but few insights into the use of indeterminate range to improve infant HIV diagnosis. A systematic review and meta-analysis was conducted to evaluate the use of an indeterminate range for HIV early infant diagnosis. Published and unpublished studies from 2000 to 2018 were included. Study quality was evaluated using GRADE and QUADAS-2 criteria. A random-effects model compared various indeterminate ranges for identifying true and false positives. The review identified 32 studies with data from over 1.3 million infants across 14 countries published from 2000 to 2018. Indeterminate results accounted for 16.5% of initial non-negative test results, and 76% of indeterminate results were negative on repeat testing. Most results were from Roche tests. In the random-effects model, an indeterminate range using a polymerase chain reaction cycle threshold value of ≥33 captured over 93% of false positives while classifying fewer than 9% of true positives as indeterminate. Without the use of an indeterminate range, over 10% of infants could be incorrectly diagnosed as HIV positive if their initial test results are not confirmed. Use of an indeterminate range appears to lead to substantial improvements in the accuracy of early infant diagnosis testing and supports current recommendations to confirm all initial positive tests.


Intensive treatment of rheumatoid arthritis reduces need for dialysis due to secondary amyloidosis.
We have analysed changes in the intensity of treatment of patients with rheumatoid arthritis (RA) and its influence on the number of patients with RA and secondary amyloidosis (SA) admitted to dialysis due to end-stage renal disease. The number of visits and patients at the rheumatological outpatient clinic because of RA, the type of medication used in 1988-1997, and the number of patients with RA and SA on dialysis from 1989 to 1999 were extracted from the data set of Kuopio University Hospital. The intensity of treatment could be evaluated as the treated number of patients with RA and the number of visits at the outpatient clinic. Both the numbers increased from 1988 to 1996, patients under treatment from 201 to 550 and visits from 1091 to 2198, respectively. In 1997, the number of patients still increased (n=637), although the number of visits started to decline (n=2054), partly due to better collaboration of health centres. A marked shift from use of only symptomatic treatment or one disease-modifying antirheumatic drug (DMARD) to more common use of immunosuppressants and/or combinations of at least two DMARDs occurred in the five years from 1992 to 1997. In 1988, the figures for only nonsteroidal anti-inflammatory drugs or only glucocorticoids or one immunosuppressive drug were 24%, 8%, and 9%, and in 1997, 4%, 3%, and 22%, respectively. In 1997, 43% of the patients were treated with combinations of two or more DMARDs. The number of patients with RA on dialysis treatment and the number of new admissions each year due to SA decreased from 11 to 2 and from 5 to none, respectively. At the beginning of year 2000 there was only one patient with RA and SA on dialysis.


Crossed Pontine Hemiatrophy Associated with Unilateral Cerebellar Hemorrhage in Premature Infants.
Background Cerebellar hemorrhage is a complication of extreme prematurity with a significant impact on the neurodevelopmental outcome. It has been shown that cerebellar hemorrhage is associated with a reduction in the anteroposterior diameter of the pons on the midline sagittal plane at term-equivalent age, suggesting that cerebellar injury may impair overall pons development in premature infants. Objective This study stemmed from an incidental observation of crossed pontine hemiatrophy in a preterm infant with a history of unilateral massive cerebellar bleeding. We aimed to verify the presence of this association in a population of preterm infants. Methods Among all, very preterm infants (GA < 32 weeks) born at our institution over a 6-year period, those with a diagnosis of unilateral massive cerebellar hemorrhage were selected. Magnetic resonance imaging scans of the selected subjects were reviewed. Results Six patients with unilateral massive cerebellar hemorrhage were identified. MRI showed crossed hemiatrophy of the pons in all cases. Conclusion Crossed hemiatrophy of the pons was associated with massive unilateral cerebellar hemorrhage. This finding may reflect retrograde degeneration of pontocerebellar fibers and loss of neurons in contralateral hemipons.


The effect of cigarette smoke and diabetes mellitus on muscarinic stimulation of prostacyclin synthesis by the rat penis.
The effect of cigarette smoke extracts and experimental diabetes on rat penile prostacyclin (PGI2) synthesis was investigated. Cigarette smoke extracts induced a dose-related inhibition of methacholine-stimulated PGI2 secretion. Induction of diabetes by streptozotocin resulted in diminished PGI2 secretion, which was further inhibited by cigarette smoke extracts in an additive fashion. Treatment with insulin prevented the inhibition of PGI2 in diabetic animals. Since PGI2 is a potent vasodilator, it may mediate the increased blood flow to the penis responsible for erection following parasympathetic stimulation. The inhibition of PGI2 secretion by cigarette smoke extracts or diabetes, or both, may therefore provide a mechanism to account for the epidemiological observation that smoking and diabetes are major risk factors for male impotence.


[Prospects for using non-invasive diagnostic techniques for assessment of cardiac rhythm variability in coronary restenosis].
The aim of the study was to evaluate dynamics of heart rhythm variability (HRV during a1, b1, and b2-adrenoblockade by carvedilol in patients with coronary heart disease (CHD) and recurrent angina pectoris treated by endovascular revascularization. The study included 39 men (mean age 57.5 +/- 0.8 years) who underwent stenting of coronary arteries (CA) 6 month or more before the study. For the purpose of analysis, patients with CA restenosis were allocated to group 1 (n = 17), those without restenosis or complaining of chest discomfort in the absence of restenosis during repeated coronaroventriculography comprised group 2 (n = 22). Patients having no complaints were followed up by coronarography 1 year after stenting. HRV was estimated from the analysis of short (15 min) fragments of the standard ECG obtained in the basal state and during a1, b1, b2-blockade by carvedilol (mean dose 22.88 +/- 2.1 mg/day) for 2 weeks. Carvedilol blockade of a1, b1, b2-adrenoreceptors following coronary stenting significantly improved both temporal and spectral components of HRV. This improvement may serve as an independent marker of revascularization efficiency and an earlier predictor of coronary restenosis or reflect progress of the atherosclerotic process in native arteries.


Maximum fluid concentrations of materials released from platelets at a surface.
We examine the estimation of local concentrations of materials that are released from the dense and alpha-granules of platelets during accumulation of platelets upon collagen-coated glass. Platelet/red blood cell suspensions were perfused through a 1.3-mm-ID tube. Empirical data were used in a calculation procedure, based on diffusion and convection, designed to yield an upper bound on the interfacial fluid concentration (IFC) for each substance considered. The necessary empirical data are the rate of platelet accumulation and the maximum amount of material in the platelet capable of secretion. It was found that the IFC is dependent on the shear rate at the surface (G) and is proportional to G0.27. This means that an eightfold increase in flow rate would increase the IFCs approximately twofold. Serotonin, pyrophosphate, adenosine 5'-monophosphate (AMP), and adenosine 5'-triphosphate (ATP) were found not to be present in sufficient quantities to produce IFCs that could influence platelet aggregation if used alone at the IFC. A second set of materials, fibrinogen, fibronectin von Willebrand factor, and calcium, had IFCs less than their concentrations normally found in plasma. A third category, containing adenosine 5'-diphosphate (ADP) alone, had an IFC close to those known to affect platelet aggregation. The role of metabolites of arachidonic acid, which may promote or inhibit platelet aggregation, awaits further description.


Integrating evaluation tools to assess nutrition education.
Evaluation is important for accountability, for planning, and for learning how to continuously refine and improve nutrition education with low-income families. The tools described in this special issue are intended to provide a resource to such evaluations. The special issue grew out of a series of USDA working groups to identify evaluation tools for nutrition education with low-income families.* I express my thanks to the many individuals who contributed to this effort.


The occlusal status of an urban and a rural Venda group.
The occlusal status of Venda school children of the town of Thohoyandou, and of a rural community in the Tshikundamalema district was determined. This comparison made it possible to eliminate racial differences as a contributing factor to malocclusions. The occlusal index of Summers was used to determine the occlusal status of 342 subjects. Positive O.I. scores were obtained for 78.9 per cent of the subjects. Twenty-eight per cent of the children required orthodontic treatment and 12 per cent treatment of a specialised nature with fixed appliances. Syndrome D (tooth displacement) occurred in 42 per cent of those requiring treatment. Class I molar relationships were seen in 96.8 per cent. The difference in positive O.I. scores between urban and rural children was highly significant (p < 0.01). The mean O.I. scores also differed significantly (p < 0.05) between the two communities. A highly significant difference (p = 0.0002) in orthodontic treatment needs was also demonstrated between urban and rural children. This study shows that environmental factors and extraction of teeth in areas where a comprehensive dental service is not available could contribute to malocclusion.


Common Features in lncRNA Annotation and Classification: A Survey.
Long non-coding RNAs (lncRNAs) are widely recognized as important regulators of gene expression. Their molecular functions range from miRNA sponging to chromatin-associated mechanisms, leading to effects in disease progression and establishing them as diagnostic and therapeutic targets. Still, only a few representatives of this diverse class of RNAs are well studied, while the vast majority is poorly described beyond the existence of their transcripts. In this review we survey common in silico approaches for lncRNA annotation. We focus on the well-established sets of features used for classification and discuss their specific advantages and weaknesses. While the available tools perform very well for the task of distinguishing coding sequence from other RNAs, we find that current methods are not well suited to distinguish lncRNAs or parts thereof from other non-protein-coding input sequences. We conclude that the distinction of lncRNAs from intronic sequences and untranslated regions of coding mRNAs remains a pressing research gap.


Ductal carcinoma in situ of the breast with different histopathological grades and corresponding new breast tumour events: analysis of loss of heterozygosity.
To compare chromosomal alterations in ductal carcinoma in situ (DCIS) of different histopathological grades and to study aberrations between primary DCIS and corresponding ipsi- or contralateral new in situ or invasive tumours, a study was undertaken of the pattern of loss of heterozygosity (LOH) at chromosomal regions in which LOH has previously been described in invasive breast cancer. LOH was analysed using 19 microsatellite markers located on chromosomes 3p, 6q, 8p, 8q, 9p, 11p, 11q, 16q, 17p, and 17q in 30 women with a primary DCIS. Eleven women with DCIS of grade 1 and 19 with grade 3 according to the EORTC classification system were included. In six patients LOH was also analysed in a subsequent new breast cancer. Fractional allelic loss (FAL, the ratio of chromosomal arms where allelic loss was detected divided by the total number of chromosomal arms with informative markers) was statistically significantly higher in grade 1 DCIS compared with grade 3 (p=0.02) for the 19 loci, indicating that the amount of allelic loss does not correlate with increasing aggressiveness of the studied tumours. Also observed was a complete heterogeneity of LOH in the primary DCIS and their corresponding new events, suggesting that these events probably developed from genetically divergent clones.


Size Matters: Defining Critical in Bone Defect Size!
Bone defects are common and are associated with a significant burden of disease. The treatment of these injuries remains controversial, particularly those defects which are critical sized. Despite the need for decision making to be evidence based, a lack of consensus around definitions of critical-sized defects still exists, particularly around those defects in the 1-3 cm range. There is a need to define "critical" in bone defect size because noncritical defects may heal without planned reconstruction and secondary surgery. This article reviews the current evidence around the definition of a critical-sized bone defect and concludes that defects in the order of 2.5 cm or greater seem to have a poor natural history.


Accuracy and Precision of Haptic Robotic-Guided Implant Surgery in Large Consecutive Series.
The purpose of this clinical study was to determine the accuracy of dental implant placement by using haptic robotic guidance in a large clinical series. In a prospective single-arm clinical study, 108 patients received 273 individual endosteal implants. A virtual preoperative restorative and surgical plan was created from a cone beam computed tomography (CBCT) scan and matched to the surgical workspace on the day of surgery via either a tooth-based or a bone-based fiducial splint. Intraoperatively, the surgeon manipulated a handpiece attached to haptic robotic guidance arm. A variety of drills and implants were used in this series. Both the osteotomy and the implant placement were guided by 3D haptic constraints according to the virtual plan. A postoperative CBCT scans permitted the calculation of the deviations of the actual implant placement compared to the plan for accuracy. Precision was calculated by comparing standard deviations from published literature. The implants were evenly distributed by jaw with 47% placed in the maxilla and 53% in the mandible. The mean ± standard deviation signed depth deviation was 0.14 ± 0.87 mm proud. The global angular deviation averaged 1.42 ± 1.53 degrees with 95% confidence limits of 1.24 degrees and 1.60 degrees. The crown of the actual placed implant showed an average deviation from the plan of 1.10 ± 0.69 mm and the apex a deviation of 1.12 ± 0.69 mm. Haptic robotic-guidance showed greater precision than freehand, static computer-guided and dynamic computer-guided implant placement. This large clinical series of 273 implants shows a high accuracy of implant placement in comparison to published accuracy for angular deviations for any technology as well as demonstrating statistically greater precision. Long-term clinical studies are necessary to establish the true effect of increased accuracy on clinical outcomes. Using haptic robotic guidance provides accurate implant placement while allowing additional benefits compared to computer-guided surgery, namely full visualization of the surgical field and the ability to change the plan intra-operatively.


A 100-200 MHz ultrasound biomicroscope.
The development of higher frequency ultrasound imaging systems affords a unique opportunity to visualize living tissue at the microscopic level. This work was undertaken to assess the potential of ultrasound imaging in vivo using the 100-200 MHz range. Spherically focused lithium niobate transducers were fabricated. The properties of a 200 MHz center frequency device are described in detail. This transducer showed good sensitivity with an insertion loss of 18 dB at 200 MHz. Resolution of 14 /spl mu/m in the lateral direction and 12 /spl mu/m in the axial direction was achieved with f/1.14 focusing. A linear mechanical scan system and a scan converter were used to generate B-scan images at a frame rate up to 12 frames per second. System performance in B-mode imaging is limited by frequency dependent attenuation in tissues. An alternative technique, zone-focus image collection, was investigated to extend depth of field. Images of coronary arteries, the eye, and skin are presented along with some preliminary correlations with histology. These results demonstrate the feasibility of ultrasound biomicroscopy In the 100-200 MHz range. Further development of ultrasound backscatter imaging at frequencies up to and above 200 MHz will contribute valuable information about tissue microstructure.


Metabolomic Biomarker Signatures for Bipolar and Unipolar Depression.
Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD) because of overlapping symptoms and the lack of objective diagnostic tools. To identify a reproducible metabolomic biomarker signature in patient dried blood spots (DBSs) that differentiates BD from MDD during depressive episodes and assess its added value when combined with self-reported patient information. This diagnostic analysis used samples and data from the Delta study, conducted in the UK between April 27, 2018, and February 6, 2020. The primary objective was to identify BD in patients with a recent (within the past 5 years) diagnosis of MDD and current depressive symptoms (Patient Health Questionnaire-9 score of 5 or more). Participants were recruited online through voluntary response sampling. The analysis was carried out between February 2022 and July 2023. Patient data were collected using a purpose-built online questionnaire (n = 635 questions). DBS metabolites (n = 630) were analyzed using a targeted mass spectrometry-based platform. Mood disorder diagnoses were established using the Composite International Diagnostic Interview. Of 241 patients in the discovery cohort, 170 (70.5%) were female; 67 (27.8%) were subsequently diagnosed with BD and 174 (72.2%) were confirmed as having MDD; and the mean (SD) age was 28.1 (7.1) years. Of 30 participants in the validation cohort, 16 (53%) were female; 9 (30%) were diagnosed with BD and 21 (70%) with MDD; and the mean (SD) age was 25.4 (6.3) years. DBS metabolite levels were assessed in 241 patients with depressive symptoms with a recent diagnosis of MDD, of whom 67 were subsequently diagnosed with BD by the Composite International Diagnostic Interview and 174 were confirmed as having MDD. The identified 17-biomarker panel provided a mean (SD) cross-validated area under the receiver operating characteristic curve (AUROC) of 0.71 (SD, 0.12; P < .001), with ceramide d18:0/24:1 emerging as the strongest biomarker. Combining biomarker data with patient-reported information significantly enhanced diagnostic performance of models based on extensive demographic data, PHQ-9 scores, and the outcomes from the Mood Disorder Questionnaire. The identified biomarkers were correlated primarily with lifetime manic symptoms and were validated in a separate group of patients who received a new clinical diagnosis of MDD (n = 21) or BD (n = 9) during the study's 1-year follow-up period, with a mean (SD) AUROC of 0.73 (0.06; P < .001). This study provides a proof of concept for developing an accessible biomarker test to facilitate the differential diagnosis of BD and MDD and highlights the potential involvement of ceramides in the pathophysiological mechanisms of mood disorders.


Surface discharges on natural dielectrics in the solar system.
When Earth-orbiting spacecraft are exposed to large fluxes of energetic charged particles, electric discharges occur on circuit boards, solar panels, and other dielectric surfaces. Large fluxes of energetic partides can produce such discharges on natural materials in the solar system. Surface discharges will occur under a variety of conditions, but particularly favorable environments are expected to occur within the magnetospheres of the giant planets; an example is the surface of Io.


Spatiotemporal Changes of Cerebral Monocarboxylate Transporter 8 Expression.
Background: Mutations of monocarboxylate transporter 8 (MCT8), a thyroid hormone (TH)-specific transmembrane transporter, cause a severe neurodevelopmental disorder, the Allan-Herndon-Dudley syndrome. In MCT8 deficiency, TH is not able to reach those areas of the brain where TH uptake depends on MCT8. Currently, therapeutic options for MCT8-deficient patients are missing, as TH treatment is not successful in improving neurological deficits. Available data on MCT8 protein and transcript levels indicate complex expression patterns in neural tissue depending on species, brain region, sex, and age. However, information on human MCT8 expression is still scattered and additional efforts are needed to map sites of MCT8 expression in neurovascular units and neural tissue. This is of importance because new therapeutic strategies for this disease are urgently needed. Methods: To identify regions and time windows of MCT8 expression, we used highly specific antibodies against MCT8 to perform immunofluorescence labeling of postnatal murine brains, adult human brain tissue, and human cerebral organoids. Results: Qualitative and quantitative analyses of murine brain samples revealed stable levels of MCT8 protein expression in endothelial cells of the blood-brain barrier (BBB), choroid plexus epithelial cells, and tanycytes during postnatal development. Conversely, the neuronal MCT8 protein expression that was robustly detectable in specific brain regions of young mice strongly declined with age. Similarly, MCT8 immunoreactivity in adult human brain tissue was largely confined to endothelial cells of the BBB. Recently, cerebral organoids emerged as promising models of human neural development and our first analyses of forebrain-like organoids revealed MCT8 expression in early neuronal progenitor cell populations. Conclusions: With respect to MCT8-deficient conditions, our analyses not only strongly support the contention that the BBB presents a lifelong barrier to TH uptake but also highlight the need to decipher the TH transport role of MCT8 in early neuronal cell populations in more detail. Improving the understanding of the spatiotemporal expression in latter barriers will be critical for therapeutic strategies addressing MCT8 deficiency in the future.


The structure of ions and zwitterionic lipids regulates the charge of dipolar membranes.
In pure water, zwitterionic lipids form lamellar phases with an equilibrium water gap on the order of 2 to 3 nm as a result of the dominating van der Waals attraction between dipolar bilayers. Monovalent ions can swell those neutral lamellae by a small amount. Divalent ions can adsorb onto dipolar membranes and charge them. Using solution X-ray scattering, we studied how the structure of ions and zwitterionic lipids regulates the charge of dipolar membranes. We found that unlike monovalent ions that weakly interact with all of the examined dipolar membranes, divalent and trivalent ions adsorb onto membranes containing lipids with saturated tails, with an association constant on the order of ∼10 M(-1). One double bond in the lipid tail is sufficient to prevent divalent ion adsorption. We suggest that this behavior is due to the relatively loose packing of lipids with unsaturated tails that increases the area per lipid headgroup, enabling their free rotation. Divalent ion adsorption links two lipids and limits their free rotation. The ion-dipole interaction gained by the adsorption of the ions onto unsaturated membranes is insufficient to compensate for the loss of headgroup free-rotational entropy. The ion-dipole interaction is stronger for cations with a higher valence. Nevertheless, polyamines behave as monovalent ions near dipolar interfaces in the sense that they interact weakly with the membrane surface, whereas in the bulk their behavior is similar to that of multivalent cations. Advanced data analysis and comparison with theory provide insight into the structure and interactions between ion-induced regulated charged interfaces. This study models biologically relevant interactions between cell membranes and various ions and the manner in which the lipid structure governs those interactions. The ability to monitor these interactions creates a tool for probing systems that are more complex and forms the basis for controlling the interactions between dipolar membranes and charged proteins or biopolymers for encapsulation and delivery applications.


YRA1 autoregulation requires nuclear export and cytoplasmic Edc3p-mediated degradation of its pre-mRNA.
Autoregulatory loops often provide precise control of the level of expression of specific genes that encode key regulatory proteins. Here we have defined a pathway by which Yra1p, a yeast mRNA export factor, controls its own expression. We show that YRA1 exon 1 sequences in cis and Yra1p in trans inhibit YRA1 pre-mRNA splicing and commit the pre-mRNA to nuclear export. Mex67p and Crm1p jointly promote YRA1 pre-mRNA export, and once in the cytoplasm, the pre-mRNA is degraded by a 5' to 3' decay mechanism that is dependent on the decapping activator Edc3p and on specific sequences in the YRA1 intron. These results illustrate how common steps in the nuclear processing, export, and degradation of a transcript can be uniquely combined to control the expression of a specific gene and suggest that Edc3p-mediated decay may have additional regulatory functions in eukaryotic cells.


An anatomic study of nipple position and areola size in Asian men.
In planning gender-reassignment surgery for biological women and treating men with gynecomastia, surgeons must have a thorough understanding of anatomically correct nipple positions and appropriate areola sizes in men. The authors sought to determine whether body height or body mass index (BMI) affects nipple position or areola size in men. Anatomic measurements of the nipples and areolae of 50 Japanese men were obtained. A relative coordinate system was defined, where the medial-lateral and superior-inferior positions of the nipple were quantitatively indicated by distance ratios between anatomic landmarks. Nipple positions were evaluated for each patient by referring to this coordinate system, and the positions were compared between groups categorized by body height or BMI. Nipple position was not significantly affected by body height. However, the nipple tended to be located more laterally in participants with higher BMI. The vertical nipple position differed between standing and supine positions. Tall men had larger areolae than short men; however, areola size did not differ with respect to BMI. Nipple position and areola size vary by body shape. Consideration of the differences is recommended when performing procedures such as female-to-male gender-reassignment surgery or correction of gynecomastia.


Six sessions of sprint interval training increases muscle oxidative potential and cycle endurance capacity in humans.
Parra et al. (Acta Physiol. Scand 169: 157-165, 2000) showed that 2 wk of daily sprint interval training (SIT) increased citrate synthase (CS) maximal activity but did not change "anaerobic" work capacity, possibly because of chronic fatigue induced by daily training. The effect of fewer SIT sessions on muscle oxidative potential is unknown, and aside from changes in peak oxygen uptake (Vo(2 peak)), no study has examined the effect of SIT on "aerobic" exercise capacity. We tested the hypothesis that six sessions of SIT, performed over 2 wk with 1-2 days rest between sessions to promote recovery, would increase CS maximal activity and endurance capacity during cycling at approximately 80% Vo(2 peak). Eight recreationally active subjects [age = 22 +/- 1 yr; Vo(2 peak) = 45 +/- 3 ml.kg(-1).min(-1) (mean +/- SE)] were studied before and 3 days after SIT. Each training session consisted of four to seven "all-out" 30-s Wingate tests with 4 min of recovery. After SIT, CS maximal activity increased by 38% (5.5 +/- 1.0 vs. 4.0 +/- 0.7 mmol.kg protein(-1).h(-1)) and resting muscle glycogen content increased by 26% (614 +/- 39 vs. 489 +/- 57 mmol/kg dry wt) (both P < 0.05). Most strikingly, cycle endurance capacity increased by 100% after SIT (51 +/- 11 vs. 26 +/- 5 min; P < 0.05), despite no change in Vo(2 peak). The coefficient of variation for the cycle test was 12.0%, and a control group (n = 8) showed no change in performance when tested approximately 2 wk apart without SIT. We conclude that short sprint interval training (approximately 15 min of intense exercise over 2 wk) increased muscle oxidative potential and doubled endurance capacity during intense aerobic cycling in recreationally active individuals.


Developing a Cell-Microcarrier Tissue-Engineered Product for Muscle Repair Using a Bioreactor System.
Fecal incontinence, although not life-threatening, has a high impact on the economy and patient quality of life. So far, available treatments are based on both surgical and nonsurgical approaches. These can range from changes in diet, to bowel training, or sacral nerve stimulation, but none of which provides a long-term solution. New regenerative medicine-based therapies are emerging, which aim at regenerating the sphincter muscle and restoring continence. Usually, these consist of the administration of a suspension of expanded skeletal-derived muscle cells (SkMDCs) to the damaged site. However, this strategy often results in a reduced cell viability due to the need for cell harvesting from the expansion platform, as well as the non-native use of a cell suspension to deliver the anchorage-dependent cells. In this study, we propose the proof-of-concept for the bioprocessing of a new cell delivery method for the treatment of fecal incontinence, obtained by a scalable two-step process. First, patient-isolated SkMDCs were expanded using planar static culture systems. Second, by using a single-use PBS-MINI Vertical-Wheel® bioreactor, the expanded SkMDCs were combined with biocompatible and biodegradable (i.e., directly implantable) poly(lactic-co-glycolic acid) microcarriers prepared by thermally induced phase separation. This process allowed for up to 80% efficiency of SkMDCs to attach to the microcarriers. Importantly, SkMDCs were viable during all the process and maintained their myogenic features (e.g., expression of the CD56 marker) after adhesion and culture on the microcarriers. When SkMDC-containing microcarriers were placed on a culture dish, cells were able to migrate from the microcarriers onto the culture surface and differentiate into multinucleated myotubes, which highlights their potential to regenerate the damaged sphincter muscle after administration into the patient. Overall, this study proposes an innovative method to attach SkMDCs to biodegradable microcarriers, which can provide a new treatment for fecal incontinence.